Developmental Changes in Progenitor Cell Responsiveness to Bone Morphogenetic Proteins Differentially Modulate Progressive CNS Lineage Fate

Abstract

Although multipotent progenitor cells capable of generating neurons, astrocytes and oligodendrocytes are present within the germinal zones of the brain throughout embryonic, postnatal and adult life, the different neural cell types are generated within discrete temporospatial developmental windows. This might suggest that multipotent progenitor cells encounter different signals during each developmental stage, thus accounting for separate waves of lineage commitment and cellular differentiation. This study demonstrates, however, that progenitor cell responses to the same class of signals, the bone morphogenetic proteins (BMPs), change during ontogeny, and that these same signals may thus initiate progenitor cell elaboration of several different lineages. BMPs promote cell death and inhibit the proliferation of early (embryonic day 13, E13) ventricular zone progenitor cells. At later embryonic (E16) stages of cerebral cortical development, BMPs exhibit a concentration-dependent dissociation of cellular actions, with either enhancement of neuronal and astroglial elaboration (at 1–10 ng/ml) or potentiation of cell death (at 100 ng/ml). Finally, during the period of perinatal cortical gliogenesis, BMPs enhance astroglial lineage elaboration. By contrast, oligodendroglial lineage elaboration is inhibited by the BMPs at all stages. Further, application of the BMP antagonist noggin to cultured progenitors promotes the generation of oligodendrocytes, indicating that endogenous BMP signaling can actively suppress oligodendrogliogenesis. These observations suggest that developmental changes in neural progenitor cell responsiveness to the BMPs may represent a novel mechanism for orchestrating context-specific cellular events such as lineage elaboration and cellular viability.

Signaling by Bone Morphogenetic Proteins and Smad1 Modulates the Postnatal Differentiation of Cerebellar Cells

“…Other studies have found that the effects of BMPs can be age and tissue dependent (Grinspan et al, 2000;Mehler et al, 2000). Although BMP promoted both neuronal and astroglial differentiation when applied to cultures of cortical cells plated at E16, BMP2 induced neuronal cell death at earlier ages (Mabie et al, 1999).…”

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…At early stages of neurogenesis, exposing stem cells and progenitor cells in the telencephalic VZ to BMP-2 or BMP-4 increases apoptosis and inhibits proliferation, whereas at later stages BMP-2 or BMP-4 signaling promotes neuronal differentiation by inducing the expression of the neuron-specific class II b-tubulin (Tuj1) through activation of the Erk mitogenactivated protein kinase (MAPK) pathway Mabie et al 1999;Mehler et al 2000;Moon et al 2009). Forebrain explants exposed to BMP-4 downregulate anterior neural gene expression, and deletion of BMP antagonists causes loss of anterior brain structures (Furuta et al 1997;Anderson et al 2002).…”

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

“…Previous studies have reported that neural progenitor cells of the adult SVZ can be driven to astrocytic phenotype by bone morphogenetic proteins (BMPs), in particular BMP-2 and BMP-4 [130][131][132]. High concentrations of these BMPs and their receptors have been identified in the SVZ of the adult rat brain [130,132] and may dictate the glial bias of newly generated cells in the adult subependyma.…”

“…High concentrations of these BMPs and their receptors have been identified in the SVZ of the adult rat brain [130,132] and may dictate the glial bias of newly generated cells in the adult subependyma. Yet at the same time, ventricular ependymal cells can express Noggin, an endogenous antagonist of the BMP family, thereby defining local niches that may remain permissive for neuronal cell fate [133][134][135][136].…”